Manual notes created because provider deep research was unavailable in this run.
timeout 180 just deep-research-falcon human PSEN2 --fallback perplexity-lite
stayed silent and timed out without writing an artifact. Publication caching was
refreshed separately with just fetch-gene-pmids human PSEN2 and confirmed all
18 PSEN2 review PMIDs were already cached. Per project instructions, no
provider-named deep-research file was written manually.
Core biology: PSEN2 encodes presenilin-2, a catalytic presenilin isoform in the
gamma-secretase complex. Gamma-secretase cleaves membrane substrates including
APP and Notch PMID:15274632. Direct PSEN2 mutagenesis supports the catalytic annotation:
the two PS2 transmembrane aspartates are critical for gamma-secretase activity
PMID:10652302.
Substrate biology: PSEN2 participates in APP processing and Notch signaling.
The D366A catalytic-site mutation caused deficits in APP proteolytic processing
PMID:10497236 and also impaired Notch signaling
PMID:10497236.
PSEN2-specific localization: compared with PSEN1, PSEN2-containing
gamma-secretase has strong late endosome/lysosome enrichment. The Cell paper
identifies a PSEN2 sorting motif that directs the complex to late
endosomes/lysosomes through AP-1 PMID:27293189 and
states that PSEN2 selectively cleaves substrates in those compartments
PMID:27293189. This supports accepting late endosome/lysosome annotations as
core localization context and treating repeated pathway-level plasma membrane
annotations cautiously.
Calcium and MAM biology: PSEN2 has evidence for ER-mitochondria calcium
coupling and membrane-contact effects PMID:21285369. For GO review,
calcium ion homeostasis, regulation of mitochondrial calcium import, and
mitochondria-associated ER membrane-contact annotations were retained as
non-core rather than promoted into the core function.
Knowledge gaps to curate:
Review update: completed first-pass review of all 79 seeded GO annotations.
Final action distribution after validation: 40 ACCEPT, 24 KEEP_AS_NON_CORE, 11
MARK_AS_OVER_ANNOTATED, and 4 UNDECIDED. just validate human PSEN2 passes
cleanly.
Second-pass audit confirmed the core PSEN2 framing: PSEN2 is a catalytic
presenilin isoform in gamma-secretase complexes, with PSEN2-specific
late-endosome/lysosome enrichment and substrate specificity. The YAML now records
manual reference_review metadata for PMID:15274632, PMID:10497236,
PMID:10652302, PMID:27293189, and PMID:21285369.
No annotation actions were changed in this pass. The four remaining UNDECIDED
annotations are response to hypoxia and three electronically inferred synaptic
location terms. The local evidence supports PSEN2 endolysosomal localization in
neuronal contexts, but not specific synaptic vesicle, presynaptic membrane, or
synaptic membrane localization; these should remain UNDECIDED pending stronger
direct evidence.